Exosomal miR-125b-5p derived from mesenchymal stromal/stem cell enhances anti-PD-1 therapy in mouse colon cancer model.

Abstract

Background: There is compelling evidence that FoxP3⁺ regulatory T cells (Tregs) play a critical role in promoting tumor immune evasion. Our prior research demonstrated that the expression of miR-125b-5p directly inhibits Tregs by targeting TNFR2 and FoxP3. Given the significant therapeutic potential of mesenchymal stromal/stem cell (MSC)-derived exosomes (MSC-EXO) in cancer treatment, the potential role of MSC-EXO in augmenting anti-tumor immunotherapy through the delivery of miR-125b-5p remains unexplored.

Methods: Nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) were employed to characterize exosomes derived from MSCs. Flow cytometry analysis was conducted to investigate the function of exosomal miR-125b-5p both in vitro and in vivo. Mouse MC38 tumor models were administrated MSC-derived exosomes containing miR-125b-5p via tail vein injection, with or without the concurrent injection (intraperitoneally, i.p.) of anti-PD-1 antibodies.

Results: Our results indicated that exosomal miR-125b-5p derived from MSC significantly inhibited the expansion, proliferation and suppressive function of Tregs in vitro. Moreover, we observed a marked reduction in tumor growth in mice treated with exosomal miR-125b-5p. Notably, while anti-PD-1 therapy alone achieved a cure rate of approximately 30% in a mouse model of colon cancer, the combined administration of exosomal miR-125b-5p significantly enhanced the therapeutic efficacy, resulting in a more than two- to three-fold increase in tumor regression in approximately 80% of the treated mice. The underlying cellular mechanism was closely associated with the reduction of tumor-infiltrating Tregs. and the increase of CD8⁺ cytotoxic T lymphocytes (CTLs).

Conclusions: In summary, our findings suggest that exosomal miR-125b-5p derived from MSC exerts prominent potential in advancing anti-PD-1 therapy by modulating tumor immune environment. This property of miR-125b-5p may be therapeutically harnessed in human cancers to enhance the efficacy of immunotherapy.